HBV genotyping

12/21/07Carrie Marshall

• Received a send-out request for HBV genotyping on a 52y man

Hepatitis B Genotyping

• Is this a mistake?• What difference does it make?• Isn’t everyone getting vaccinated

anyway?

• While chronic Hep B is not common in the US, there are 350-400 million patients world wide

• New studies suggest that the genotype can play a part in the prediction of acute liver disease, development of HCC and/or cirrhosis, and response to antivirals

• Test requests will likely increase in the future

• Hepatitis B Virus is divided into eight genotypes (A through H) based upon genetic variation

• If there is greater than 8% divergence at the DNA sequence level, then it is a separate genotype

• The geographical distribution of genotypes is unequal (your genotype depends on your ethnicity and place of birth)

• East Asia Types B and C• Europe Types A and D• India Types A and D• Africa Types A, D, and E• United States predominately A

– West 75% B and C– Southeast 63% A– Midwest 69% A and C

• In areas of the world where chronic HBV infection is the most common, there is also less variability of genotypes (hard to see if there is a difference between groups)

• In the US, where all 8 genotypes are found, there are fewer patients to enroll into studies

Clinical Concerns

• Patients with chronic HBV have a 15%-25% lifetime risk of developing HCC and/or cirrhosis (NEJM 2004)

• Who should be monitored? How frequently? How aggressively? (CT, MRI, Bx?)

• Some evidence that Genotype C has a higher risk for progressing to cirrhosis, and is less responsive to interferon therapy

Natural History of HBVSerology Viral Load ALT level

1. Immune Tolerance

eAg + High Normal

2. Immune Clearance

eAg + High Increased

3. Carrier State

eAg –Anti eAb +

Low(<2000 IU)10 K copies/ml

Normal

4. Reactivation

e Ag –Anti e Ab +

High Increased

So what do we want to know about the patient in question?

• Audience participation

Natural History of HBVSerology Viral Load ALT level

1. Immune Tolerance

eAg + High Normal

2. Immune Clearance

eAg + High Increased

3. Carrier State

eAg –Anti eAb +

Low(<2000 IU)10 K copies/ml

Normal

4. Reactivation

e Ag –Anti e Ab +

High Increased

Is that True?

• Sometimes. That is probably the way it goes for genotypes A and D.

• Testing for HBVeAg and HBVeAb (~$7.00) is a good way to follow those patients, in combination with ALT

• But genotypes B and C there is an association with 2 mutations which interfere with the production of HBVeAg

• Pre-core mutation will prevent the expression of HBVeAg, without changing the ability of the virus to replicate and is associated with genotypes D (55%), B (44%) and C (22%)

• Rare in genotype A (3%)• Numbers based on a US study• Overall in the US, 27% of patients

with Chronic HBV have a precore mutation (will not express HBVeAg)

• Core promoter mutation can lead to a reduced production of HBVeAg, and is associated with genotypes C (60%), A (41%) and D (40%)

• Least common in genotype B (26%)• Again these are US numbers• Overall in the US, 44% of patients with

Chronic HBV have a core promoter mutation

• Mixed results on whether these mutations lead to more injury, or higher viral loads

What does this mean?

• Should there be a change in the way chronic HBV patients are followed?

• Should we just follow viral load ($252)?

• Should everyone get genotyped ($134)?

• Should patients (or only HBVeAg -) patients be tested for PC/CP mutations?

I don’t know!

• Serial viral loads would be ideal, but costs a lot more.

• Maybe just LFTs are good enough? Certainly patients with high viral loads and increased LFTs are at risk for cirrhosis/HCC, but not so clear what the risk is for patients with high viral loads but normal LFTs

• Genotyping would be a one-time (?) expense, and could guide the decision to treat, and choice of therapy– Could also predict the likelihood of a PC/CP

mutation (and the non-usefulness of following HBVeAg)

I couldn’t find convincing evidence that PC/CP mutations have an effect on therapy, and/or risk of cirrhosis and HCC

Related Reading

• Chu CJ et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology, 2003;125:444-451.

• Chu CJ et al. Prevalance of HBV precore/core promoter variants in the United States. Hepatology, 2003;38(3):619-628.

Related Reading

• Grandjacques C et al. Rapid detection of genotypes and mutations in the pre-core promoter and the pre-core region of hepatitis B virus genome: correlation with viral persistence and disease severity. Journal of hepatology, 2000;33:430-439.

• Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: A longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline. Journal of hepatology, 2005;43:411-417.